The Need for Myeloma Treatment
A diagnosis of multiple myeloma (MM) requires an extensive medical evaluation looking at blood and urine testing, radiologic imaging, and tissue (bone marrow) biopsy. The results of these tests may indicate a precursor condition known as smoldering multiple myeloma (SMM). However, if SLiM CRAB criteria, also known as myeloma defining events (MDE), are found, the next step will be to discuss treatment options.
Resources: Learning About Myeloma Treatment
- What Are MGUS, Smoldering Myeloma, and MM?
- Tip Card: Early Warning Signs
- What is multiple myeloma?
- Patient Handbook
- Understanding Myeloma Vocabulary
- What Tests Do You Need?
How Is Multiple Myeloma Treated?
The current treatment landscape for myeloma involves combinations of medications to get the deepest and most durable response. When needed, medication combinations will be adjusted or changed for continued management. Each new combination is referred to as a line of therapy (LOT). The first LOT for active myeloma is commonly referred to as initial, frontline, or induction treatment.
When Should You Begin Treatment for Your Multiple Myeloma?
For some people, starting treatment comes after close surveillance for smoldering myeloma that has progressed to active myeloma. For others, treatment begins after evaluation of symptoms arising from CRAB features that have led to a diagnosis of myeloma. Although it is important to get treatment started to prevent further medical complications such as infections, kidney or bone damage, there may be time to discuss treatment options available including participating in a clinical trial.
Sometimes, emergency situations may require immediate medical attention. Kidney failure, high blood calcium, active infection or vertebral fracture that presses on the nerves or spinal cord are examples of emergency situations that require immediate intervention. Treatment is directed at the immediate medical issue in effort to preserve renal function, reduce blood calcium, treat infection, and/or reduce pressure on the spinal cord. Supportive care measures are used in parallel with myeloma treatment to get the disease and symptoms under control.
Resources: Starting Treatment
- Patient Handbook
- Urgent Problems at Diagnosis
- Understanding Your Test Results
- Understanding Clinical Trials in Myeloma
Why Should You Consult with a Myeloma Expert?
Myeloma is a complex diagnosis with rapidly changing treatment options. Adding a myeloma expert to your care team can help with answering your questions, gaining access to clinical trials, and becoming aware of future treatment options. Health care providers that specialize in myeloma care can work with your local hematologist, review your plan of care, and provide additional recommendations.
Frontline Treatment Options for Multiple Myeloma
The Use of Four Drugs for Frontline Treatment
Treatment for multiple myeloma continues to evolve. In 2024, results from key research studies provided updates to frontline therapy, incorporating quadruplet (4 drugs) as standard of care (SOC) treatment. These SOC options are based upon the results of phase III trials in which a treatment regimen was shown to be better than other therapies. The phase III trial results updated the SOC for both transplant and transplant ineligible (TI) patients.
For Transplant-Eligible Patients
For younger and fit individuals, frontline therapy is a three-step process that makes up one line of therapy (LOT): Induction, autologous stem cell transplant (ASCT), and maintenance.
Induction: As of July 30, 2024, the United States Food and Drug Administration (U.S. FDA) approved Darzalex (daratumumab or dara) in combination with Velcade (bortezoimb), Revlimid (lenalidomide) and dexamethasone (Dara-VRd or D-VRd). This approval was based on results from the PERSEUS trial (NCT03710603) and marks D-VRd as the SOC induction therapy for newly diagnosed multiple myeloma patients who are eligible for autologous stem cell transplant.
Results from the PERSEUS trial show statistically significant benefit in progression-free survival (PFS) and depth of response, both complete response (CR) and minimal residual disease (MRD)-negative status (MRDneg), when dara is added to VRd:
| D-VRd | VRd | |
| PFS (48 months) | 84.3% | 67.7% |
| CR or better | 87.9% | 70.1% |
|
MRDneg (10-5) MRDneg (10-6) |
75.2% 65.1% |
47.5% 32.2% |
The PERSEUS study confirms the clinical benefits of adding daratumumab to standard VRd therapy. It shows significant improvements in depth of response and long-term disease control, supporting its use in combination regimens for newly diagnosed multiple myeloma patients.
Daratumumab in combination with VRd is considered the preferred regimen by the National Comprehensive Cancer Network (NCCN) guidelines for primary treatment of myeloma for those who are transplant candidates.
These drugs are administered as follows:
- Darzalex (daratumumab) is given by subcutaneous injection
- Velcade (bortezomib) is given by subcutaneous injection
- Revlimid (lenalidomide) is a pill taken by mouth
- Dexamethasone, a steroid taken as a pill by mouth or can be given intravenous (IV)
Kyprolis (carfilzomib) combined with Revlimid (lenalidomide) and dexamethasone, KRd, may be used instead of VRd in patients with higher risk features such as FISH abnormalities and/or plasma cell leukemia or myeloma occurring in soft tissue areas (extramedullary—or outside the bone). For patients that have, or are at high risk for, peripheral neuropathy Kyprolis (carfilzomib) may be used instead of Velcade (bortezomib). Adding Darzalex (daratumumab) to the KRd combination may also be an option recommended by your care team.
Revlimid (lenalidomide) may be replaced due to medical need or drug availability. Alternative combinations for frontline therapy for people considered eligible for ASCT include:
- Darzalex, Velcade, Thalomid® (thalidomide), and dexamethasone (DVTd): This combination is administered like the DVRd combination. Thalomid is an immunomodulatory drug (IMiD) and can be taken as a pill by mouth as well.
- Darzalex, Velcade, Cytoxan® (cyclophosphamide), dexamethasone (DVCd or Dara-CyBorD). Cytoxan is an alkylating agent that can be taken as a pill by mouth.
- Darzalex, Velcade, dexamethasone (DVd)
Before undergoing ASCT, a person will receive 4-6 cycles of induction therapy to gain control over myeloma cells and to show the myeloma is responsive to therapy.
ASCT: Use of autologous stem cell transplant (ASCT) in the upfront setting is part of a multi-step treatment plan and is considered SOC. Alkeran (Melphalan) is intensive chemotherapy and is given IV. There are additional steps to this process involving eligibility determination, stem cell collection, high-dose chemotherapy followed by stem cell infusion, engraftment, and recovery.
Maintenance: Following recovery from ASCT, approximately 2-3 months, use of maintenance therapy to maintain control over myeloma is recommended. Medications used for induction are also used for maintenance with changes in dose and schedule.
Current SOC does not put a time limit or duration of use for maintenance therapy; however, discontinuation may be considered after 2 years if bone marrow minimal residual disease (MRD) results remain negative with repeat testing. This is an important discussion to have with your myeloma specialist.
Resources: Four-drug Combination for Transplant-Eligible Patients
- Understanding DARZALEX and DARZALEX FASPRO
- Understanding the VRd Regimen for Newly Diagnosed Myeloma
- Understanding Stem Cell Transplant in Myeloma
- Understanding KYPROLIS® (carfilzomib) for Injection
- Tip Card: Alkylating Agents
- Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. (Sonneveld, et al., NEJM, 2024;390(4):301-313.)
For Transplant-Ineligible Patients
ASCT is a rigorous treatment process; not all people will be eligible or able to undergo this process due to frailty or age. Some may choose to delay or decline ASCT based on personal circumstances and preferences.
There are a variety of treatment combinations available. As of September 20, 2024, the U.S. FDA approved Sarclisa (isatuximab) combined with VRd as quadruplet therapy for those people not eligible for transplant. This approval is based on the results from two key phase III trials: IMROZ and BENEFIT.
The IMROZ phase III trial (NCT03319667) evaluated the quadruplet combination of isatuximab with bortezomib, lenalidomide, and dexamethasone (Isa-VRd) compared to the triplet combination of bortezomib, lenalidomide, and dexamethasone (VRd) in patients with newly diagnosed multiple myeloma (NDMM) who are transplant-ineligible (TI).
The addition of isatuximab to the VRd regimen also shows statistically significant benefit in progression-free survival (PFS) and depth of response, both complete response (CR) and minimal residual disease (MRD)-negative status (MRDneg), when Sarclisa (isatuximab) is added to VRd.
| Isa-VRd | VRd | |
| PFS (60 months) | 63.2% | 45.2% |
| CR or better | 74.7% | 64.1% |
|
MRDneg (10-5) |
55.5% |
40.9% |
The BENEFIT phase III trial (NCT04751877) reinforced the use of the quadruplet combination of Isa-VRd as the new SOC for TI patients by comparing Isa-VRd to Isa-Rd. By adding Velcade (bortezomib), complete response and MRD-negativity rates were higher as compared to the Isa-Rd group.
| Isa-VRd | VRd | |
| PFS (24 months estimated*) | 85.2% | 80% |
| CR or better (18 months) | 58% | 33% |
|
MRDneg (10-5) 18 months |
53% |
26% |
*Data are still immature.
Sarclisa (isatuximab) in combination with VRd is included in the National Comprehensive Cancer Network (NCCN) guidelines for primary treatment of multiple myeloma for transplant and non-transplant candidates.
Additional combination options include:
- Revlimid and dexamethasone (Rd)
- Velcade and dexamethasone (Vd)
- VRd Lite, which means the patient will take a VRd regimen with lighter doses of each drug to improve tolerance
- DRd, the MAIA regimen: Darzalex® (daratumumab), Revlimid, and dexamethasone
Resources: Four-drug combinations for Transplant-Ineligible Patients
- Tip Card: Sarclisa®
- Understanding the VRd Regimen for Newly Diagnosed Myeloma
- Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma (Facon, et al. NEJM, 2024)
- Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: the randomized phase 3 BENEFIT trial (Leleu, et al. Nat Med, 2024)
What Are the Expectations of Frontline Treatment?
Most patients will experience an excellent response to induction therapy that occurs within the first 2-3 months of treatment. This response is tracked by measuring the myeloma protein levels (free lite chains, M-spike, or M-protein) each month. The myeloma has responded if there has been at least a fifty-percent reduction in myeloma protein levels. This is considered a partial response (PR).
When response continues to 90%, it is known as a very good partial response, or VGPR. If the response shows a 100% reduction in M-protein— such that the M-protein or free lite chains are no longer detectable by traditional methods (SPEP or IFE tests), then it is known as complete response or CR.
The expectation of frontline therapy is that response will last, on average, 4-5 years, especially for patients with “standard risk” myeloma. For people with “high risk” features, in whom remission has lasted less than one year, adjustment to frontline therapy should be made to improve response. For example, your doctor may substitute Kyprolis® (carfilzomib) in DVRd to make DKRd with plans for ongoing therapy for myeloma control.
Improvement in Myeloma Symptoms
Typically, myeloma symptoms improve with response to treatment. For example, CRAB features (Calcium levels, Renal/Kidney function, Anemia, and Bone disease) correct during the first months of treatment leading to improvement in symptoms. It may be helpful for you to keep a symptom diary to track changes (improvement or worsening) to inform your healthcare team. Your healthcare team will repeat blood tests to monitor calcium, creatinine (kidney function), and hemoglobin levels (anemia), as well as monitor response to treatment. Additional imaging studies (X-rays, MRIs, or CT scans) may also be recommended by your doctor.
If significant bone damage has occurred, associated pain and other issues may take longer to resolve. Use of radiation therapy, interventional procedures (i.e. vertebroplasty, kyphoplasty, surgery) and pain medication may be needed to manage acute and long-term pain. Bone strengthening medications are used to quickly reduce high calcium levels and reduce the risk of future bone loss and fracture.
Resources: Managing Myeloma Symptoms and Complications
- Understanding Your Test Results
- Understanding Fatigue
- Understanding Treatment of Myeloma Bone Disease
- Understanding Treatment of Myeloma-Induced Vertebral Compression Fractures
What Are Side Effects of Myeloma Treatments?
Typically, D-VRd or alternate combinations are very well tolerated. Close monitoring for any signs or symptoms of infection is of greatest importance, especially in the first few weeks of therapy. During this time, the immune system is compromised because of both myeloma and the treatment. As the treatment begins to destroy the myeloma cells, the immune system becomes more effective. Yet, the treatment has a continued immunocompromising effect. Changes in appetite (increase and decrease), bowel function (constipation and diarrhea), and nerve damage (neuropathy) are possible and can increase over time. As mentioned, maintain a symptom diary and report side effects to your healthcare team.
Resources: Gain a Better Understanding of Myeloma Drugs
Myeloma and Treatment Decision-Making
A diagnosis of multiple myeloma and starting treatment is overwhelming for you and your loved ones. Understanding your treatment options, how they may affect your quality of life, and what matters most to you are key to participating in shared decision-making with your doctor and healthcare team. Together, you will consider the treatment options, including benefits and side effects.
Be sure to discuss expectations for quality of life, the impact on your career if you are still working, and the impact of treatment on other life activities. The cost of care may also be a consideration for you.
You, as part of your healthcare team, will need to come to a treatment decision that best manages the myeloma while aligning with your values and preferences.
Resources: Improve Your Doctors' Visits with These Tools
- Tip Card: Myeloma Treatment Discussion Tool
- Tip Card: Ask Your Doctor These Important Questions
- Comprehensive Glossary
What's Next?
Learn about what factors you and your healthcare team should consider to determine if you are eligible for a stem cell transplant. Also, gain an understanding of the transplant procedure.
The International Myeloma Foundation medical and editorial content team
Comprised of leading medical researchers, hematologists, oncologists, oncology-certified nurses, medical editors, and medical journalists, our team has extensive knowledge of the multiple myeloma treatment and care landscape.
Additionally, the content on this page is medically reviewed by myeloma physicians and healthcare professionals.
Last Medical Content Review: October 14, 2024